Fibronectin III domain of IL-11Rα

Abstract

The present disclosure provides proteins comprising antigen binding sites of antibodies that bind to interleukin-11 (IL-11) receptor alpha (IL-11Rα) and uses thereof, e.g., in therapy.

The invention claimed is: 
     
       1. An isolated or recombinant IL-11Rα-binding protein comprising an antigen binding domain of an antibody, wherein the antigen binding domain specifically binds to IL-11Rα and neutralizes IL-11 signaling, and the antigen binding domain binds to an epitope comprising residues within the first fibronectin III domain of IL-11Rα, wherein the first fibronectin III domain comprises amino acids 111-215 of SEQ ID NO: 1, and wherein the antigen binding domain comprises a heavy chain variable region (V H ) comprising a sequence set forth in SEQ ID NO: 71 and a light chain variable region (V L ), the V L  comprising: 
       (i) a complementarity determining region (CDR) 1 comprising a sequence set forth between amino acids 24-34 of SEQ ID NO: 5 optionally comprising six or fewer amino acid substitutions, a CDR2 comprising a sequence set forth between amino acids 50-56 of SEQ ID NO: 5 and a CDR3 comprising a sequence set forth between amino acids 89-97 of SEQ ID NO: 5 optionally comprising five or fewer amino acid substitutions; or 
       (ii) a sequence at least about 94% identical to a sequence set forth in SEQ ID NO: 5. 
     
     
       2. The IL-11Rα-binding protein of  claim 1 , wherein the amino acid substitution(s) in CDR1 of the V L  are within the six C-terminal residues of the CDR1 and/or the amino acid substitution(s) of the V L  are within the six N-terminal or the six C-terminal residues of the CDR3. 
     
     
       3. The IL-11Rα-binding protein of  claim 1 , wherein the antigen binding domain comprises a V H  comprising a sequence set forth in SEQ ID NO: 72. 
     
     
       4. The IL-11Rα-binding protein of  claim 1  wherein the antigen binding domain comprises:
 (i) a V H  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 37 (optionally, also comprising the amino acid N-terminal to CDR1) and a V L  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 5; 
 (ii) a V H  comprising a sequence set forth in SEQ ID NO: 37 and a V L  comprising a sequence set forth in SEQ ID NO: 5; 
 (iii) a V H  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 38 (optionally, also comprising the amino acid N-terminal to CDR1) and a V L  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 5; 
 (iv) a V H  comprising a sequence set forth in SEQ ID NO: 38 and a V L  comprising a sequence set forth in SEQ ID NO: 5; 
 (v) a V H  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 39 (optionally, also comprising the amino acid N-terminal to CDR1) and a V L  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 5; 
 (vi) a V H  comprising a sequence set forth in SEQ ID NO: 39 and a V L  comprising a sequence set forth in SEQ ID NO: 5; 
 (vii) a V H  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 40 (optionally, also comprising the amino acid N-terminal to CDR1) and a V L  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 5; 
 (viii) a V H  comprising a sequence set forth in SEQ ID NO: 40 and a V L  comprising a sequence set forth in SEQ ID NO: 5; 
 (ix) a V H  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 41 (optionally, also comprising the amino acid N-terminal to CDR1) and a V L  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 5; 
 (x) a V H  comprising a sequence set forth in SEQ ID NO: 41 and a V L  comprising a sequence set forth in SEQ ID NO: 5; 
 (xi) a V H  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 42 (optionally, also comprising the amino acid N-terminal to CDR1) and a V L  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 5; 
 (xii) a V H  comprising a sequence set forth in SEQ ID NO: 42 and a V L  comprising a sequence set forth in SEQ ID NO: 5; 
 (xiii) a V H  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 43 (optionally, also comprising the amino acid N-terminal to CDR1) and a V L  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 5; 
 (xiv) a V H  comprising a sequence set forth in SEQ ID NO: 43 and a V L  comprising a sequence set forth in SEQ ID NO: 5; 
 (xv) a V H  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 44 (optionally, also comprising the amino acid N-terminal to CDR1) and a V L  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 5; 
 (xvi) a V H  comprising a sequence set forth in SEQ ID NO: 44 and a V L  comprising a sequence set forth in SEQ ID NO: 5; 
 (xvii) a V H  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 45 (optionally, also comprising the amino acid N-terminal to CDR1) and a V L  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 5; 
 (xviii) a V H  comprising a sequence set forth in SEQ ID NO: 45 and a V L  comprising a sequence set forth in SEQ ID NO: 5; 
 (xix) a V H  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 46 (optionally, also comprising the amino acid N-terminal to CDR1) and a V L  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 5; 
 (xx) a V H  comprising a sequence set forth in SEQ ID NO: 46 and a V L  comprising a sequence set forth in SEQ ID NO: 5; 
 (xxi) a V H  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 47 (optionally, also comprising the amino acid N-terminal to CDR1) and a V L  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 5; 
 (xxii) a V H  comprising a sequence set forth in SEQ ID NO: 47 and a V L  comprising a sequence set forth in SEQ ID NO: 5; 
 (xxiii) a V H  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 48 (optionally, also comprising the amino acid N-terminal to CDR1) and a V L  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 5; 
 (xxiv) a V H  comprising a sequence set forth in SEQ ID NO: 48 and a V L  comprising a sequence set forth in SEQ ID NO: 5; 
 (xxv) a V H  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 49 (optionally, also comprising the amino acid N-terminal to CDR1) and a V L  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 5; 
 (xxvi) a V H  comprising a sequence set forth in SEQ ID NO: 49 and a V L  comprising a sequence set forth in SEQ ID NO: 5; 
 (xxvii) a V H  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 50 (optionally, also comprising the amino acid N-terminal to CDR1) and a V L  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 5; 
 (xxviii) a V H  comprising a sequence set forth in SEQ ID NO: 50 and a V L  comprising a sequence set forth in SEQ ID NO: 5; 
 (xxix) a V H  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 51 (optionally, also comprising the amino acid N-terminal to CDR1) and a V L  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 5; 
 (xxx) a V H  comprising a sequence set forth in SEQ ID NO: 51 and a V L  comprising a sequence set forth in SEQ ID NO: 5; 
 (xxxi) a V H  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 52 (optionally, also comprising the amino acid N-terminal to CDR1) and a V L  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 5; 
 (xxxii) a V H  comprising a sequence set forth in SEQ ID NO: 52 and a V L  comprising a sequence set forth in SEQ ID NO: 5; 
 (xxxiii) a V H  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 53 (optionally, also comprising the amino acid N-terminal to CDR1) and a V L  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 5; 
 (xxxiv) a V H  comprising a sequence set forth in SEQ ID NO: 53 and a V L  comprising a sequence set forth in SEQ ID NO: 5; 
 (xxxv) a V H  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 54 (optionally, also comprising the amino acid N-terminal to CDR1) and a V L  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 5; 
 (xxxvi) a V H  comprising a sequence set forth in SEQ ID NO: 54 and a V L  comprising a sequence set forth in SEQ ID NO: 5; 
 (xxxvii) a V H  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 55 (optionally, also comprising the amino acid N-terminal to CDR1) and a V L  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 5; 
 (xxxviii) a V H  comprising a sequence set forth in SEQ ID NO: 55 and a V L  comprising a sequence set forth in SEQ ID NO: 5; 
 (xxxix) a V H  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 56 (optionally, also comprising the amino acid N-terminal to CDR1) and a V L  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 5; 
 (xl) a V H  comprising a sequence set forth in SEQ ID NO: 56 and a V L  comprising a sequence set forth in SEQ ID NO: 5; 
 (xli) a V H  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 57 (optionally, also comprising the amino acid N-terminal to CDR1) and a V L  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 5; 
 (xlii) a V H  comprising a sequence set forth in SEQ ID NO: 57 and a V L  comprising a sequence set forth in SEQ ID NO: 5; 
 (xliii) a V H  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 58 (optionally, also comprising the amino acid N-terminal to CDR1) and a V L  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 5; 
 (xliv) a V H  comprising a sequence set forth in SEQ ID NO: 58 and a V L  comprising a sequence set forth in SEQ ID NO: 5; 
 (xlv) a V H  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 59 (optionally, also comprising the amino acid N-terminal to CDR1) and a V L  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 5; 
 (xlvi) a V H  comprising a sequence set forth in SEQ ID NO: 59 and a V L  comprising a sequence set forth in SEQ ID NO: 5; 
 (xlvii) a V H  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 60 (optionally, also comprising the amino acid N-terminal to CDR1) and a V L  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 5; 
 (xlviii) a V H  comprising a sequence set forth in SEQ ID NO: 60 and a V L  comprising a sequence set forth in SEQ ID NO: 5; 
 (xlix) a V H  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 61 (optionally, also comprising the amino acid N-terminal to CDR1) and a V L  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 5; 
 (l) a V H  comprising a sequence set forth in SEQ ID NO: 61 and a V L  comprising a sequence set forth in SEQ ID NO: 5; 
 (li) a V H  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 62 (optionally, also comprising the amino acid N-terminal to CDR1) and a V L  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 5; 
 (lii) a V H  comprising a sequence set forth in SEQ ID NO: 62 and a V L  comprising a sequence set forth in SEQ ID NO: 5; 
 (liii) a V H  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 63 (optionally, also comprising the amino acid N-terminal to CDR1) and a V L  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 5; 
 (liv) a V H  comprising a sequence set forth in SEQ ID NO: 63 and a V L  comprising a sequence set forth in SEQ ID NO: 5; 
 (lv) a V H  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 64 (optionally, also comprising the amino acid N-terminal to CDR1) and a V L  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 5; 
 (lvi) a V H  comprising a sequence set forth in SEQ ID NO: 64 and a V L  comprising a sequence set forth in SEQ ID NO: 5; 
 (lvii) a V H  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 65 (optionally, also comprising the amino acid N-terminal to CDR1) and a V L  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 5; 
 (lviii) a V H  comprising a sequence set forth in SEQ ID NO: 65 and a V L  comprising a sequence set forth in SEQ ID NO: 5; 
 (lix) a V H  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 66 (optionally, also comprising the amino acid N-terminal to CDR1) and a V L  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 5; 
 (lx) a V H  comprising a sequence set forth in SEQ ID NO: 66 and a V L  comprising a sequence set forth in SEQ ID NO: 5; 
 (lxi) a V H  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 67 (optionally, also comprising the amino acid N-terminal to CDR1) and a V L  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 5; 
 (lxii) a V H  comprising a sequence set forth in SEQ ID NO: 67 and a V L  comprising a sequence set forth in SEQ ID NO: 5; 
 (lxiii) a V H  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 68 (optionally, also comprising the amino acid N-terminal to CDR1) and a V L  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 5; 
 (lxiv) a V H  comprising a sequence set forth in SEQ ID NO: 68 and a V L  comprising a sequence set forth in SEQ ID NO: 5; 
 (lxv) a V H  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 69 (optionally, also comprising the amino acid N-terminal to CDR1) and a V L  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 5; 
 (lxvi) a V H  comprising a sequence set forth in SEQ ID NO: 69 and a V L  comprising a sequence set forth in SEQ ID NO: 5; 
 (lxvii) a V H  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 70 (optionally, also comprising the amino acid N-terminal to CDR1) and a V L  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 5; 
 (lxviii) a V H  comprising a sequence set forth in SEQ ID NO: 37 and a V L  comprising a sequence set forth in SEQ ID NO: 5; 
 (lxix) a V H  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 70 (optionally, also comprising the amino acid N-terminal to CDR1) and a V L  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 5; or 
 (lxx) a V H  comprising a sequence set forth in SEQ ID NO: 70 and a V L  comprising a sequence set forth in SEQ ID NO: 5. 
 
     
     
       5. The IL-11Rα-binding protein of  claim 1 , wherein the antigen binding domain comprises:
 (i) a V H  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 49 (optionally, also comprising the amino acid N-terminal to CDR1) and a V L  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 5; 
 (ii) a V H  comprising a sequence set forth in SEQ ID NO: 49 and a V L  comprising a sequence set forth in SEQ ID NO: 5; 
 (iii) a V H  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 53 (optionally, also comprising the amino acid N-terminal to CDR1) and a V L  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 5; 
 (iv) a V H  comprising a sequence set forth in SEQ ID NO: 53 and a V L  comprising a sequence set forth in SEQ ID NO: 5; 
 (v) a V H  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 57 (optionally, also comprising the amino acid N-terminal to CDR1) and a V L  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 5; 
 (vi) a V H  comprising a sequence set forth in SEQ ID NO: 57 and a V L  comprising a sequence set forth in SEQ ID NO: 5; 
 (vii) a V H  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 58 (optionally, also comprising the amino acid N-terminal to CDR1) and a V L  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 5; or 
 (viii) a V H  comprising a sequence set forth in SEQ ID NO: 58 and a V L  comprising a sequence set forth in SEQ ID NO: 5. 
 
     
     
       6. The IL-11Rα-binding protein of  claim 1 , wherein the V H  and V L  bind to form a Fv comprising an antigen binding domain, wherein the V H  and the V L  are in a single polypeptide chain or the V L  and V H  are in separate polypeptide chains. 
     
     
       7. The IL-11Rα-binding protein of  claim 6 , wherein if the V H  and V L  are in a single polypeptide chain, the protein is:
 (i) a single chain Fv fragment (scFv); 
 (ii) a dimeric scFv (di-scFv); 
 (iii) one of (i) or (ii) linked to a constant region of an antibody, Fc or a heavy chain constant domain (C H ) 2 and/or C H 3; or 
 (iv) one of (i) or (ii) linked to a protein that binds to an immune effector cell, or if the V H  and V L  are in separate polypeptide chains the protein is: 
 (i) a diabody; 
 (ii) a triabody; 
 (iii) a tetrabody; 
 (iv) a Fab; 
 (v) a F(ab′) 2 ; 
 (vi) a Fv; 
 (vii) one of (i) to (vi) linked to a constant region of an antibody, Fc or a heavy chain constant domain (C H ) 2 and/or C H 3; 
 (viii) one of (i) to (vi) linked to a protein that binds to an immune effector cell; or 
 (ix) an antibody. 
 
     
     
       8. The IL-11Rα-binding protein of  claim 7 , which is an antibody comprising:
 (i) a V H  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 49 (optionally, also comprising the amino acid N-terminal to CDR1) and a V L  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 5; 
 (ii) a V H  comprising a sequence set forth in SEQ ID NO: 49 and a V L  comprising a sequence set forth in SEQ ID NO: 5; 
 (iii) a V H  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 53 (optionally, also comprising the amino acid N-terminal to CDR1) and a V L  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 5; 
 (iv) a V H  comprising a sequence set forth in SEQ ID NO: 53 and a V L  comprising a sequence set forth in SEQ ID NO: 5; 
 (v) a V H  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 57 (optionally, also comprising the amino acid N-terminal to CDR1) and a V L  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 5; 
 (vi) a V H  comprising a sequence set forth in SEQ ID NO: 57 and a V L  comprising a sequence set forth in SEQ ID NO: 5; 
 (vii) a V H  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 58 (optionally, also comprising the amino acid N-terminal to CDR1) and a V L  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 5; or 
 (viii) a V H  comprising a sequence set forth in SEQ ID NO: 58 and a V L  comprising a sequence set forth in SEQ ID NO: 5. 
 
     
     
       9. The IL-11Rα-binding protein of  claim 8 , additionally comprising a constant region of an IgG4 antibody or a stabilized constant region of an IgG4 antibody comprising a proline at position 241 according to the numbering system of Kabat, wherein the constant region optionally lacks a C-terminal lysine residue. 
     
     
       10. The IL-11Rα-binding protein of  claim 7 , which is an antibody comprising:
 (i) a V H  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 37 (optionally, also comprising the amino acid N-terminal to CDR1) and a V L  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 18; or 
 (ii) a V H  comprising a sequence set forth in SEQ ID NO: 37 and a V L  comprising a sequence set forth in SEQ ID NO: 18. 
 
     
     
       11. The IL-11Rα-binding protein of  claim 10  additionally comprising a constant region of an IgG4 antibody or a stabilized constant region of an IgG4 antibody comprising a proline at position 241 according to the numbering system of Kabat, wherein the constant region optionally lacks a C-terminal lysine residue. 
     
     
       12. An isolated or recombinant IL-11Rα-binding protein comprising an antigen binding domain of an antibody, wherein the antigen binding domain specifically binds to IL-11Rα and neutralizes IL-11 signaling, and wherein the antigen binding domain comprises a heavy chain variable region (V H ) and a light chain variable region (V L ) as follows:
 (i) a V H  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 76 (optionally, also comprising the amino acid N-terminal to CDR1) and a V L  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 75; 
 (ii) a V H  comprising a sequence set forth in SEQ ID NO: 76 and a V L  comprising a sequence set forth in SEQ ID NO: 75; 
 (iii) a V H  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 74 (optionally, also comprising the amino acid N-terminal to CDR1) and a V L  comprising CDRs 1, 2 and 3 of a sequence set forth in SEQ ID NO: 73; 
 (iv) a V H  comprising a sequence set forth in SEQ ID NO: 74 and a V L  comprising a sequence set forth in SEQ ID NO: 73. 
 
     
     
       13. The IL-11Rα-binding protein of  claim 1 , which is conjugated to another compound. 
     
     
       14. A composition comprising the IL-11Rα-binding protein of  claim 1  and a pharmaceutically acceptable carrier.